Experimental change in temperament: Conversion of the low exploratory phenotype into highly explorative by...

Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high-anxiety/low-motivation, we have found that overexpression of glial cell line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector completely converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of the behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key regulators of monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, suggestive of a reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of temperament/personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.