Low levels of serotonin in the brain are known to play a role in depression and anxiety, the involvement of serotonin (5-HT) in regulating emotional behaviour is firmly established. In fact, molecules that boost 5-HT signaling are the most frequently prescribed psychiatric drugs on the market, with a primary indication for the treatment of depression and anxiety disorders. These drugs mainly increase 5-HT signaling by blocking 5-HT reuptake or degradation.
However, insight into the direct role of 5-HTergic neuronal activity on behaviour remains scarce and conflicting. For example, several animal models of anxiety and depression-like behaviour display reduced firing of 5-HTergic neurons, implying a causal relationship, yet genetic blockade of 5-HTergic vesicular neurotransmission reduces anxiety. Now, a study from researchers at Columbia University has shown that neighbouring serotonin-producing brainstem regions exert different and sometimes opposing effects on behaviour. The team state that their findings provide new insights into the development of mood disorders and may aid in designing improved therapies. The opensource study is published in the journal published today Cell Reports.
Previous studies show that the brainstem contains two distinct clusters of serotonergic neurons, one in dorsal raphe nucleus (DRN) and another in the median raphe nucleus (MRN). Together both regions harbor the vast majority of neurons that supply serotonin to the rest of the brain, however, it was unclear how neuronal activity within these clusters controls behaviour. The current study shows that alterations in serotonergic neuronal activity in the DRN and MRN produce markedly different behavioural consequences.
The current study used a technique called pharmacogenetics to control the activity of serotonergic neurons in the DRN and MRN in both normal mice and in a mouse model of depression- and anxiety-like behaviour. Results show that hyperactivity of the MRN drives anxiety-like behaviour. Data findings also show that decreased DRN activity increases depression-like behaviour, while decreased MRN activity reduces it The lab state that this suggests that an imbalance between DRN and MRN activity is what leads to depression-like behaviour.
The group also demonstrated, in experiments using the fluoxetine-treated mice, that inhibition of serotonin reuptake early in life leads to long-lasting imbalances between the DRN and MRN. The lab state that this raises possible concerns about exposure to serotonin-specific reuptake inhibitors during gestation; SSRIs cross the blood-brain barrier as well as the placenta, and bind maternal and fetal serotonin transporters alike. They go on to add that it’s too early to say whether this has any effect on behaviour in humans, however, it’s certainly something worth looking into
The team surmise that this new understanding of the raphe nuclei should help the global community better understand why certain medications are effective in treating depression and anxiety, and aid in designing new drugs. They go on to state that neurobiological studies such as this are essential to elucidate the molecular mechanisms of antidepressant treatments. For the future, the researchers state that it may be possible to find treatments that selectively target the DRN or the MRN, or that correct any imbalance between the two.
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