Diabetes Causes Dysfunctional Dopamine Neurotransmission Favoring Nigrostriatal Degeneration in Mice

This article also appears in: Special Collection: COVID-19 Resources.[Background]: Numerous studies indicate an association between neurodegenerative and metabolic diseases. Although still a matter of debate, growing evidence from epidemiological and animal studies indicate that preexisting diabetes increases the risk to develop Parkinson's disease. However, the mechanisms of such an association are unknown.[Objectives]: We investigated whether diabetes alters striatal dopamine neurotransmission and assessed the vulnerability of nigrostriatal neurons to neurodegeneration.[Methods]: We used streptozotocin‐treated and genetically diabetic db/db mice. Expression of oxidative stress and nigrostriatal neuronal markers and levels of dopamine and its metabolites were monitored. Dopamine release and uptake were assessed using fast‐scan cyclic voltammetry. 6‐Hydroxydopamine was unilaterally injected into the striatum using stereotaxic surgery. Motor performance was scored using specific tests.[Results]: Diabetes resulted in oxidative stress and decreased levels of dopamine and its metabolites in the striatum. Levels of proteins regulating dopamine release and uptake, including the dopamine transporter, the Girk2 potassium channel, the vesicular monoamine transporter 2, and the presynaptic vesicle protein synaptobrevin‐2, were decreased in diabetic mice. Electrically evoked levels of extracellular dopamine in the striatum were enhanced, and altered dopamine uptake was observed. Striatal microinjections of a subthreshold dose of the neurotoxin 6‐hydroxydopamine in diabetic mice, insufficient to cause motor alterations in nondiabetic animals, resulted in motor impairment, higher loss of striatal dopaminergic axons, and decreased neuronal cell bodies in the substantia nigra.[Conclusions]: Our results indicate that diabetes promotes striatal oxidative stress, alters dopamine neurotransmission, and increases vulnerability to neurodegenerative damage leading to motor impairment.Funded by the Spanish Ministries of Economy and Competitiveness (grants BFU2014‐52149‐R and BFU2017‐89336‐R to M.V., SAF2016‐78207‐R and PCIN‐2015‐098 to R.M., and BFU2017‐88393‐P to E.D.M.) and of Health, Social Services and Equality (PNSD‐2016I033 to R.M.) and by the Ramón Areces Foundation (ref. 172275 to R.M.). Supported by Medical Research Council UK iCASE award (to S.J.C., R.A.), a Biotechnology and Biological Sciences Research Council UK studentship (to S.V.M.), and Parkinson's UK (J‐1403 to S.J.C.). Partially supported by FEDER funds. CIBERDEM and CIBERNED are initiatives of the Instituto de Salud Carlos III. I.P.T. was supported by a fellowship from the Spanish Ministry of Education, Culture and Sports (FPU 14/04457).Peer reviewe

Prior experience conditionally inhibits the expression of new learning in Drosophila

Prior experience of a stimulus can inhibit subsequent acquisition or expression of a learned association of that stimulus. However, the neuronal manifestations of this learning effect, named latent inhibition (LI), are poorly understood. Here, we show that prior odor exposure can produce context-dependent LI of later appetitive olfactory memory performance in Drosophila. Odor pre-exposure forms a short-lived aversive memory whose lone expression lacks context-dependence. Acquisition of odor pre-exposure memory requires aversively reinforcing dopaminergic neurons that innervate two mushroom body compartments—one group of which exhibits increasing activity with successive odor experience. Odor-specific responses of the corresponding mushroom body output neurons are suppressed, and their output is necessary for expression of both pre-exposure memory and LI of appetitive memory. Therefore, odor pre-exposure attaches negative valence to the odor itself, and LI of appetitive memory results from a temporary and context-dependent retrieval deficit imposed by competition with the parallel short-lived aversive memory