Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice.

Metabolic homeostasis is under circadian regulation to adapt energy requirements to light-dark cycles. Feeding cycles are regulated by photic stimuli reaching the suprachiasmatic nucleus via retinohypothalamic axons and by nutritional information involving dopaminergic neurotransmission. Previously, we reported that Pitx3-mutant Aphakia mice with altered development of the retinohypothalamic tract and the dopaminergic neurons projecting to the striatum, are resistant to locomotor and metabolic entrainment by time-restricted feeding. In their Matters Arising article, Scarpa et al. (2022) challenge this conclusion using mice from the same strain but following a different experimental paradigm involving calorie restriction. Here, we address their concerns by extending the analyses of our previous data, by identifying important differences in the experimental design between both studies and by presenting additional results on the dopaminergic deficit in the brain of Aphakia mice. This Matters Arising Response article addresses the Matters Arising article by Scarpa et al. (2022), published concurrently in Cell Reports.

Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice.

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2-/- ) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2-/- mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2-/- mice. Moreover, c-Fos expression observed in D2-/- mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.

Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse.

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.

Dopamine D1 Receptors Regulate Spines in Striatal Direct-Pathway and Indirect-Pathway Neurons.

BACKGROUND: Dopamine transmission is involved in the maintenance of the structural plasticity of direct-pathway and indirect-pathway striatal projection neurons (d-SPNs and i-SPNs, respectively). The lack of dopamine in Parkinson's disease produces synaptic remodeling in both types of SPNs, reducing the length of the dendritic arbor and spine density and increasing the intrinsic excitability. Meanwhile, the elevation of dopamine levels by levodopa recovers these alterations selectively in i-SPNs. However, little is known about the specific role of the D1 receptor (D1R) in these alterations. METHODS: To explore the specific role of D1R in the synaptic remodeling of SPNs, we used knockout D1R mice (D1R-/- ) and wild-type mice crossed with drd2-enhanced green fluorescent protein (eGFP) to identify d-SPNs and i-SPNs. Corticostriatal slices were used for reconstruction of the dendritic arbors after Lucifer yellow intracellular injection and for whole-cell recordings in naïve and parkinsonian mice treated with saline or levodopa. RESULTS: The genetic inactivation of D1R reduces the length of the dendritic tree and the spine density in all SPNs, although more so in d-SPNs, which also increases their spiking. In parkinsonian D1R-/- mice, the spine density decreases in i-SPNs, and this spine loss recovers after chronic levodopa. CONCLUSIONS: D1R is essential for the maintenance of spine plasticity in d-SPNs but also affects i-SPNs, indicating an important crosstalk between these 2 types of neurons. © 2020 International Parkinson and Movement Disorder Society.