Characterization of striatal dopamine projections across striatal subregions in behavioral flexibility.

Behavioural flexibility is key to survival in a dynamic environmentWhile flexible, goal-directed behaviours are initially dependent on dorsomedial striatum, they become dependent on lateral striatum as behaviours become inflexible. Similarly, lesions of dopamine terminals in lateral striatum disrupt the development of inflexible habits. This work suggests that dopamine release in lateral striatum may drive inflexible behaviours, though few studies have investigated a causative role of subpopulations of striatal dopamine terminals in reversal learning, a measure of flexibility. Here, we performed two optogenetic experiments to activate dopamine terminals in dorsomedial (DMS), dorsolateral (DLS) or ventral (nucleus accumbens [NAc]) striatum in DAT-Cre mice that expressed channelrhodopsin-2 via viral injection (Experiment I) or through transgenic breeding with an Ai32 reporter line (Experiment II) to determine how specific dopamine subpopulations impact reversal learning. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Largely consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating medial dopamine terminals reversed lever preference following contingency reversal, while mice self-stimulating NAc showed parial flexibility, and DLS self-stimulation resulted in impaired reversal. Impairments in DLS mice were characterized by more regressive errors and reliance on lose-stay strategies following reversal, as well as reduced within-session learning, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which DMS and ventral dopamine facilitate goal-directed responding, and DLS dopamine supports more inflexible responding.

Cannabidiol (CBD) drives sex-dependent impairments in omission, but has no effect on reinforcer devaluation.

Habits are inflexible behaviors that persist despite changes in outcome value. While habits allow for efficient responding, neuropsychiatric diseases such as drug addiction and obsessive-compulsive disorder are characterized by overreliance on habits. Recently, the commercially popular drug cannabidiol (CBD) has emerged as a potential treatment for addictive behaviors, though it is not entirely clear how it exerts this therapeutic effect. As brain endocannabinoids play a key role in habit formation, we sought to determine how CBD modifies goal-directed behaviors and habit formation. To explore this, mice were administered CBD (20 mg/kg i.p.) or vehicle as a control and trained on random interval (RI30/60) or random ratio (RR10/20) schedules designed to elicit habitual or goal-directed lever pressing, respectively. Mice were tested for habitual responding using probe trials following reinforcer-specific devaluation as well as omission trials, where mice had to withhold responding to earn rewards. We found that while CBD had little effect on operant behaviors or reward devaluation, CBD inhibited goal-directed behavior in a sex-specific and context dependent manner during the omission task. Beyond drug treatment, we found an effect of sex throughout training, reward devaluation, and omission. This work provides evidence that CBD has no effect on habit formation in a reward devaluation paradigm. However, the omission results suggest that CBD may slow learning of novel action outcome contingencies or decrease goal-directed behavior. This work calls for further examination of sex-dependent outcomes of CBD treatment and highlights the importance of investigating sex effects in habit-related experiments.

Age dependence of retinal vascular plexus attenuation in the triple transgenic mouse model of Alzheimer's disease.

The influence of Alzheimer's disease (AD) progression and severity on the structural and functional integrity of the cerebral vasculature is well recognized. The retina is an extension of the brain; thus, changes in retinal vascular features may serve as markers of AD cerebrovascular pathologies. However, differentiating normal aging-versus AD-induced retinal vascular changes is unresolved. Therefore, we compared and quantified changes in superficial (SVP), intermediate (IVP), and deep (DVP) retinal vascular plexuses in young, middle-age, and old triple transgenic mouse model of AD (3xT-AD) to the changes that occur in age-matched controls (C57BL/6j). We used immunostaining combined with a novel tissue optical clearing approach along with a computational tool for quantitative analysis of vascular network alterations (vessel length and density) in SVP, IVP, and DVP. All three layers had comparable structural features and densities in young 3xTg-AD and control animals. In controls, IVP and DVP densities decreased with aging (-14% to -32% change from young to old, p < 0.05), while no changes were observed in SVP. In contrast, vascular parameters in the transgenic group decreased in all three layers with aging (-12% to -49% change from young to old, p < 0.05). Furthermore, in the old group, SVP and DVP vascular parameters were lower in the transgenics compared to age-matched controls (p < 0.05). Our analysis demonstrates that normal aging and progression of AD lead to various degrees of vascular alterations in the retina. Specifically, compared to normal aging, changes in vascular features of SVP and DVP regions of the retina are accelerated during AD progression. Considering recent advances in the field of depth-resolved imaging of retinal capillary network and microangiography, noninvasive quantitative monitoring of changes in retinal vascular network parameters of SVP and DVP may serve as markers for diagnosis and staging of Alzheimer's disease and discriminating AD-induced vascular attenuation from age-related vasculopathy.