The Lack of Dopamine Transporter Is Associated With Conditional Associative Learning Impairments and Striatal Proteomic Changes

Abstract

Dopamine (DA) is critically involved in different functions of the central nervous system (CNS) including control of voluntary movement, affect, reward, sleep, and cognition. One of the key components of DA neurotransmission is DA reuptake by the DA transporter (DAT), ensuring rapid clearance of DA from the synaptic cleft. Thus, lack of DAT leads to persistent high extracellular DA levels. While there is strong evidence for a role of striatal dopaminergic activity in learning and memory processes, little is known about the contribution of DAT deficiency to conditional learning impairments and underlying molecular processes. DAT-knockout (DAT-KO) rats were tested in a set of behavioral experiments evaluating conditional associative learning, which requires unaltered striatal function. In parallel, a large-scale proteomic analysis of the striatum was performed to identify molecular factors probably underlying behavioral patterns. DAT-KO rats were incapable to acquire a new operant skill in Pavlovian/instrumental autoshaping, although the conditional stimulus–unconditional stimulus (CS-US) association seems to be unaffected. These findings suggest that DAT directly or indirectly contributes to the reduction of transference of incentive salience from the reward to the CS. We propose that specific impairment of conditional learning might be caused by molecular adaptations to the hyperdopaminergic state, presumably by dopamine receptor 1 (DRD1) hypofunction, as proposed by proteomic analysis. Whether DRD1 downregulation can cause cognitive deficits in the hyperdopaminergic state is the subject of discussion, and further studies are needed to answer this question. This study may be useful for the interpretation of previous and the design of future studies in the dopamine field.

Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience

“…DAT-KO and DAT-KD learning and memory deficits were also revealed in a novel object recognition test [72,106]. Although the lack of DAT does not seem to affect simple Pavlovian conditioning [61,72,92], DAT-KO rats were incapable of learning new stimulus-response associations [61], while DAT-KO mice performed less avoidance in the Conditioned Avoidance Responding Test than WT littermates [87]. Similarly, aberrant Pavlovian-to-instrumental transfer was revealed in DAT-KD mice [92].…”

“…Additionally, changes in cortical and striatal power spectra and interareal coherence were detected [60]. Proteomic analysis revealed modifications in striatal proteins expression that were closely related to learning and memory mechanisms (i.e., synaptic transmission, axodendritic transport, and DA-binding processes) [61].…”

Rats Lacking the Dopamine Transporter Display Inflexibility in Innate and Learned Behavior

“…Abnormalities in DA-ergic system functioning lead to the development of different neurological diseases [ 7 , 8 ]. In the search for and development of new therapeutic approaches for the treatment of these diseases, different animal models were created [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Rodents (mice and rats) with a knockout of the gene encoding the dopamine reuptake transporter protein (DAT-KO) are one of the most popular models of hyperdopaminergia [ 4 , 16 , 17 , 18 ].…”

Deep learning-based image-analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.

“…It is crucial for re-uptake of dopamine at somatodendrites and axons, and also mediates electric conductances (Ryan et al, 2021). The identification of a DATnegative SN DA neuron population has not only physiological relevance (Bu et al, 2021;Miller et al, 2021;Savchenko et al, 2022), but it has additional implications, as DAT is commonly used as marker for SN DA neurons and for their specific targeting, e.g. to generate DA neuron specific knock out mice, expressing Cre-recombinase under the control of the DAT-promoter (Gong et al, 2007;Lammel et al, 2015;Papathanou et al, 2019;Stuber et al, 2015).…”